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Satoru Todo

Publications and source records attributed to Satoru Todo.

At least 37 records · Page 2Linked to original sources
PubMed2006

Identification of squamous cell carcinoma antigen-derived peptides having the capacity of inducing cancer-reactive CTLs in HLA-A24+ cancer patients.

Squamous cell carcinoma antigen (SCCA) is a useful marker for SCCs. In this study, we attempted to identify SCCA-derived peptides that could be applied in the development of specific immunotherapy for HLA-A24+ cancer patients with SCC or non-SCC. A variety of SCC and non-SCC lines were examined for their expression of SCCA mRNA using quantitative PCR. SCCA protein expression in cancer tissues was investigated by immunohistochemical staining. Thereafter, SCCA-derived peptide candidates were prepared based on their binding motifs to HLA-A24 molecules. Among these peptides, SCCA-derived peptides that were frequently recognized by humoral immunity were further tested for their ability to induce cancer-reactive cytotoxic T lymphocytes (CTLs) from the peripheral blood mononuclear cells of HLA-A24+ patients with SCC or non-SCC. As a result, the majority of SCC lines and tissues were positive for SCCA both at mRNA and protein levels. By contrast, non-SCC cancer tissues hardly expressed it at the protein level, although adenocarcinoma cell lines partly expressed it at the mRNA level. Four SCCA-derived peptides were frequently recognized by immunoglobulin G of both SCC and non-SCC cancer patients. Among these peptides, both the SCCA(112-120) and SCCA(215-224) peptides were found to effectively induce peptide-specific CTLs toward HLA-A24+ SCCA+ cancer cells from the peripheral blood mononuclear cells of both SCC and non-SCC cancer patients. Two newly identified SCCA-derived peptides with the ability to induce CTL activity in both SCC and non-SCC cancer patients may be applicable to specific immunotherapy for HLA-A24+ cancer patients with SCC, but not those with non-SCC.

Antibodies, Neoplasm↗
PubMed2006

[Efficacy and toxicity of combination treatment with epirubicin (EPI) plus docetaxel (DOC) in advanced breast cancer].

Thirty women (mean age 50.4 years, range 31-63) with primary advanced breast cancer were given EPI 40-60 mg/m(2) and DOC 50-60 mg/m(2) intravenously every three weeks. The efficacy was evaluated after 4 cycle treatments. There were 5 complete responses (CR) and 14 partial responses (PR), giving an overall response rate of 63.3%. There were 2 pathological CR (8%) which showed complete disappearance of cancer cells. The high dose group showed a better response than the low-dose group. The most common grade 3/4 adverse events were neutropenia (26.7%) and general fatigue (6.7%). The simultaneous combination treatment of EPI and DOC is effective for primary chemotherapy and can be performed safely even for outpatients.

Adult↗
PubMed2006

[Acquired tumor "robustness" in the case of prostate cancer].

Tumors are highly robust and maintain their proliferative potential against both a wide range of host-defense mechanisms and anticancer therapies. In this study, we investigated the levels of human leukocyte antigen (HLA) class I, multi-drug resistance 1 (MDR1), and androgen receptor (AR) expressions in untreated prostate cancers harvested by radical prostectomy. The mean percentages of cancer cells expressing HLA class I, MDR1, and AR among the 10 cancer samples were 41, 35, and 74%, respectively. In addition, double-staining of HLA class I and MDR1 revealed the four definite populations (HLA class I(+)/MDR(+), HLA class I(+)/MDR(-), HLA class I (-)/MDR(+), and HLA class I(-)/MDR(-)) in cancer tissues from the majority of cancer patients tested, and the mean percentages of cells expressing these combinations were 13, 29, 22, and 38%, respectively. Similar results were obtained by double staining of HLA class I and AR, except for 2 cases in which HLA class I(-)/AR (+) cancer cells predominated. These results indicated that untreated prostate cancer cells acquired a wide range of genomic mutation, which may have been caused by internal host pressure to eliminate malignant cells, and would provide evidence of the robustness of untreated prostate cancer.

Aged↗
PubMed2005

Dimeric but not monomeric soluble CD40 prolongs allograft survival and generates regulatory T cells that inhibit CTL function.

BACKGROUND: We previously reported that adenovirus mediated CD40Ig gene therapy (AdCD40Ig) induced long-term acceptance of fully allogeneic rat cardiac allografts, however, the underlying mechanism has not been fully clarified. To address this we have compared the ability of dimeric and monomeric soluble CD40 to prolong allograft survival in vivo and generate regulatory T cells in vitro. METHODS: The ability of CD40Ig (soluble dimmer, containing an Fc region) or CD40/Myc/His (soluble monomer, lacking an Fc region) therapy to generate CD4CD25 regulatory T cells in vitro and to prevent rejection of rat cardiac allografts (ACI to LEWIS) was compared. Immunoregulatory capacity of regulatory T cells generated was determined by suppression of alloantigen specific proliferation and cytotoxicity. RESULTS: Dimeric soluble CD40Ig did not inhibit CD4 T cell proliferation but rather promoted IL-2 production and the generation of CD4CD25 T cells, which regulated alloantigen-specific cytotoxic T lymphocyte activity. Treatment with either AdCD40Ig or purified soluble CD40Ig prolonged the survival of rat cardiac allografts. In contrast, although monomeric soluble CD40/Myc/His suppressed IL-12 production in a similar manner to that achieved by CD40Ig, it did not augment IL-2 production. Moreover, while CD40/Myc/His also generated CD4CD25 T cells, they did not exhibit regulatory activity and administration of soluble CD40/Myc/His failed to prolong cardiac allograft survival. CONCLUSIONS: These results suggest signaling through CD154 in addition to blocking of CD154-CD40 interaction is important for the immunomodulatory effects of soluble CD40Ig. Taken together, our results provide new insight into the mechanism of immunomodulation by soluble CD40 constructs.

Animals↗
PubMed2005

Effects of synthetic antifreeze glycoprotein analogue on islet cell survival and function during cryopreservation.

The antifreeze glycoprotein (AFGP), found in the blood of polar fish, is known to prevent ice crystal growth and to depress the freezing temperature, which may in turn protect tissues from freezing injury. The chemical synthesis of AFGP is an attractive alternative to its difficult isolation from natural sources, and this would permit quality control and mass production. In spite of recent success in islet transplantation for the treatment of type 1 diabetes mellitus, existing methods for the long-term preservation of islets are considered to be suboptimal and inadequate, which indicates the need for the development of improved methods. Rat islets were isolated from male Wistar rats, using intraductal collagenase distention, mechanical dissociation, and Ficoll-Conray gradient purification. Islets were cultured overnight and then cryopreserved in RPMI1640 in the presence of dimethyl sulfoxide (Me2SO) and 10% FCS with various concentrations of syAFGP, followed by slow cooling (0.3 degrees C/min) and rapid thawing (200 degrees C/min) as described by Rajotte. The freezing process was observed by cryomicroscopy. Islet recovery post-cryopreservation was 85.0 +/- 6.2% with syAFGP and 63.3 +/- 14.2% without syAFGP, both compared with the pre-cryopreservation counts (P < 0.05). The in vitro islet function measured by insulin release was equivalent to a static stimulation index of 3.86+/-0.43 for the islets that were frozen-and-thawed with syAFGP, compared to 2.98 +/- 0.22 without syAFGP (P < 0.05). At a concentration of around 500 microg/ml syAFGP, a strong attenuation of ice crystal growth and formation was observed by cryomicroscopy and these ice crystals did not cause cryoinjury. In conclusion, the attenuation of ice crystallization by syAFGP improves islet survival and function following cryopreservation and thawing.

Animals↗
PubMed2005

UFD2a mediates the proteasomal turnover of p73 without promoting p73 ubiquitination.

p73 protein level is kept extremely low in mammalian cultured cells and its stability may be regulated by not only the ubiquitin/proteasome-dependent proteolysis but also through other unidentified mechanisms. Here, we found for the first time that p73 is physically as well as functionally associated with the U-box-type E3/E4 ubiquitin ligase UFD2a. The immunoprecipitation experiments demonstrated that this interaction is mediated by the COOH-terminal region of p73alpha containing SAM domain. During the cisplatin-induced apoptosis in SH-SY5Y neuroblastoma cells, p73alpha accumulated at a protein level, whereas the endogenous UFD2a was significantly reduced in response to cisplatin. Ectopic expression of UFD2a decreased the half-life of p73alpha in association with a significant inhibition of the p73alpha-mediated transactivation as well as proapoptotic activity. Downregulation of endogenous UFD2a by antisense strategy resulted in a remarkable accumulation of p73alpha. Unexpectedly, UFD2a-mediated degradation of p73alpha was sensitive to the proteasomal inhibitor, however, UFD2a did not affect the ubiquitination levels of p73alpha. Taken together, our present findings imply that UFD2a might promote the proteasomal turnover of p73 in a ubiquitination-independent manner, and also suggest that UFD2a might play an important role in the regulation of cisplatin-induced apoptosis mediated by p73.

Animals↗
PubMed2005

A radical scavenger, edaravone, protects canine kidneys from ischemia-reperfusion injury after 72 hours of cold preservation and autotransplantation.

BACKGROUND: Cold ischemia-reperfusion (I/R) injury is a prominent cause of delayed graft function after kidney transplantation. Reactive oxygen species play a crucial role in I/R injury. Edaravone is a synthetic radical scavenger that has been used in acute stroke. Some animal experiments have revealed its beneficial effects against I/R injury, but its effects after cold preservation and transplantation of canine kidneys are unknown. METHODS: Female hybrid dogs weighing 11 to 13 kg were used. Under anesthesia, the left kidney was harvested. After 72 hr of preservation in cold histidine-tryptophan-ketoglutarate solution, autotransplantation was performed in the right iliac fossa, with contralateral nephrectomy. Animals were divided into control and treatment groups (n=6 per group). In the treatment group, edaravone was administered intravenously at harvest and at reperfusion (3 mg/kg) and in addition was added to the preservation solution (50 microM). RESULTS: Animal survival at 2 weeks was four of six in the control group and six of six in the treatment group. Compared with controls, treated animals had higher mean urine output, higher mean glomerular filtration rate, improved tubular cell function, lower mean serum creatinine, and lower renal vascular resistance. Biopsy specimens from treated animals showed less tubular cell damage and decreased P-selectin expression in endothelial cells. Lipid peroxidation of renal tissue and urinary excretion of 8-hydroxy-2'-deoxyguanosine were suppressed by the treatment. CONCLUSIONS: Edaravone reduced cold I/R injury in canine renal transplantation. The agent has the potential to ameliorate preservation injury in clinical transplantation.

Animals↗
PubMed2005

Compensatory recovery of liver mass by Akt-mediated hepatocellular hypertrophy in liver-specific STAT3-deficient mice.

BACKGROUND/AIMS: Liver regeneration following hepatectomy is complicated and involves a variety of interacting factors. The present study was designed to study the roles of proliferation and hypertrophy of hepatocytes in liver regeneration following hepatectomy in liver-specific STAT3-knockout (LS3-KO) mice lacking mitogenic activity. METHODS: Partial hepatectomy was performed in LS3-KO and control mice. Liver regeneration was estimated by the liver weight, cell proliferation and cell size, and the related cellular signals were analyzed. RESULTS: Proliferation of hepatocytes following PH was markedly suppressed in LS3-KO mice with reduced cyclinD1 transcript. However, liver mass recovered sufficiently following PH in LS3-KO mice almost equal to that of control mice. Analysis of hepatocellular growth revealed that cell size following hepatectomy was significantly larger in LS3-KO mice than in control mice. Hepatectomy induced immediate but transient phosphorylation of Akt, p70S6K, mTOR and GSK-3beta in LS3-KO mice much more than in control mice. Additionally, adenoviral transfection of dominant negative mutant of Akt to control and LS3-KO mice led to insufficient liver regeneration following hepatectomy. CONCLUSIONS: PI3-K/Akt-mediated responsive hepatocellular hypertrophy may be essential for liver regeneration following hepatectomy and sufficiently compensated liver regeneration even in STAT3-deficient liver, in which cell proliferation is impaired.

Animals↗
PubMed2005

Lipid peroxidation during ischemia depends on ischemia time in warm ischemia and reperfusion of rat liver.

Prolonged hepatic warm ischemia has been incriminated in oxidative stress after reperfusion. However, the magnitude of oxidative stress during ischemia has been controversial. The aims of the present study were to elucidate whether lipid peroxidation progressed during ischemia and to clarify whether oxidative stress during ischemia aggravated the oxidative damage after reperfusion. Rats were subjected to 30 to 120 min of 70% warm ischemia alone or followed by reperfusion for 60 min. Lipid peroxidation (LPO) was evaluated by amounts of phosphatidylcholine hydroperoxide (PC-OOH) and phosphatidylethanolamine hydroperoxide (PE-OOH) as primary LPO products. Total amounts of malondialdehyde and 4-hydroxy-2-nonenal (MDA + 4-HNE), degraded from hydroperoxides, were also determined. PC-OOH and PE-OOH significantly increased at 60 and 120 min ischemia with concomitant increase of oxidized glutathione. These hydroperoxides did not increase at 60 min reperfusion after 60 min ischemia, whereas they did increase at 60 min reperfusion after 120 min ischemia with deactivation of phospholipid hydroperoxide glutathione peroxidase and superoxide dismutase. The amount of MDA + 4-HNE exhibited similar changes, but the velocity of production dropped with ischemic time longer than 60 min. In conclusion, oxidative stress progressed during ischemia and triggered the oxidative injury after reperfusion. Secondary LPO products are less sensitive, especially during ischemia, which may cause possible underestimation and discrepancy.

Aldehydes↗
PubMed2005

Identification of protein kinase A catalytic subunit beta as a novel binding partner of p73 and regulation of p73 function.

Post-translational modifications play a crucial role in regulation of the protein stability and pro-apoptotic function of p53 as well as its close relative p73. Using a yeast two-hybrid screening based on the Sos recruitment system, we identified protein kinase A catalytic subunit beta (PKA-Cbeta) as a novel binding partner of p73. Co-immunoprecipitation and glutathione S-transferase pull-down assays revealed that p73alpha associated with PKA-Cbeta in mammalian cells and that their interaction was mediated by both the N- and C-terminal regions of p73alpha. In contrast, p53 failed to bind to PKA-Cbeta. In vitro phosphorylation assay demonstrated that glutathione S-transferase-p73alpha-(1-130), which has one putative PKA phosphorylation site, was phosphorylated by PKA. Enforced expression of PKA-Cbeta resulted in significant inhibition of the transactivation function and pro-apoptotic activity of p73alpha, whereas a kinase-deficient mutant of PKA-Cbeta had no detectable effect. Consistent with this notion, treatment with H-89 (an ATP analog that functions as a PKA inhibitor) reversed the dibutyryl cAMP-mediated inhibition of p73alpha. Of particular interest, PKA-Cbeta facilitated the intramolecular interaction of p73alpha, thereby masking the N-terminal transactivation domain with the C-terminal inhibitory domain. Thus, our findings indicate a PKA-Cbeta-mediated inhibitory mechanism of p73 function.

Animals↗
PubMed2005

Macrophage migration inhibitory factor promotes tumor invasion and metastasis via the Rho-dependent pathway.

PURPOSE: Macrophage migration inhibitory factor (MIF) plays an important role not only in the immune system but also in tumorigenesis. In this study, we investigated the potential role of MIF in association with tumor invasion and metastasis. METHODS: To assess the function of MIF, we knocked down the MIF mRNA using small interfering RNA (siRNA). Twenty-one base siRNA specific for the mRNA sequence of mouse MIF was introduced to a murine colon cancer cell line, colon 26. Tumor cell invasion was evaluated using a transwell method (8-microm pores) coated with Matrigel on the upperside membrane and with fibronectin on the underside membrane. Moreover, we investigated the signal transduction of lysophosphatidic acid (LPA) relevant to the Rho-dependent pathway and further examined the effect of MIF siRNA on this signal transduction system. In vivo, the tumor cells were pretreated with MIF siRNA and injected into the portal vein, and the effects on metastasis to the liver were evaluated. RESULTS: We found that MIF siRNA markedly reduced the invasion of the cells from the upperside to lowerside membranes. We revealed that the Rho-dependent pathway activated by LPA was suppressed by MIF siRNA. Next, we found that the tyrosine-phosphorylation of focal adhesion kinase and LPA-induced expressions of integrin beta1 were significantly suppressed by MIF siRNA. In vivo, metastasis to the liver was significantly inhibited by pretreatment of the cells with MIF siRNA. CONCLUSION: Taken together, these results suggest that MIF promotes tumor invasion and metastasis via the Rho-dependent pathway.

Animals↗
PubMed2005

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) who showed early massive disease recurrence due to hematogenous intrahepatic metastasis after curative resection had a poor prognosis. The authors previously reported that Akt phosphorylation was correlated with hematogenous intrahepatic metastasis, using HCC cell lines. METHODS: The authors analyzed clinicopathologic features and the status of selected biologic markers, including phosphorylated Akt, to identify risk factors for early disease recurrence and poor prognosis in HCC. In the current series, 49 postoperative patients developed intrahepatic disease recurrence within 6 months (Group 1) and 86 patients remained disease recurrence free > 3 years after resection (Group 2). Group 1 was further divided into 2 subgroups: 19 patients who died of disease recurrence within a year after resection (Group 1A) and 27 patients who survived > 1 year (Group 1B). RESULTS: Using univariate analysis, the risk factors for early disease recurrence were tumor size, macroscopic classification, tumor differentiation, microscopic capsule infiltration, microscopic portal vein (MPV) invasion, microscopic intrahepatic metastasis (MIM), and positive immunostaining for phosphorylated Akt, Ki-67, and p53 (P < 0.05). The risk factors for poor prognosis were the number of intrahepatic metastases, tumor differentiation, and positive immunostaining for phosphorylated Akt and Ki-67 (P < 0.05). Multivariate analysis revealed that the risk factors for early disease recurrence were MPV invasion, MIM, and positive immunostaining for phosphorylated Akt, and that the risk factors for poor prognosis were positive immunostaining for phosphorylated Akt and Ki-67 (P < 0.05). CONCLUSIONS: The current clinical study showed the critical involvement of Akt phosphorylation in the aggressiveness of HCC. The potential benefits of surgery should be assessed carefully in patients with any of these risk factors.

Aged↗
PubMed2005

Number of lymph node metastases is a significant prognostic factor in intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (IHCC) is a rare primary hepatic tumor. Outcomes after resection and the use of lymph node dissection have not been well described. From a prospective database, we identified 53 patients with IHCC who underwent exploration between April 1983 and March 2004. Hepatic resection was performed in 44 patients, 30 of whom underwent lymph node dissection. Clinicopathological features and outcomes were analyzed. The actuarial 1-year survival was 66.2% in resected patients, compared to 0% in unresectable patients (p < 0.0001), with a 50% overall survival of 21.5 months and 3.1 months, respectively. The actuarial 3-year and 5-year overall survival rates in resected patients were 38.3% and 26.3%, respectively. Univariate analysis revealed that factors associated with poor overall survival included multiple tumors, extrahepatic bile duct involvement, noncurative resection, and involvement of lymph nodes. Multivariate analysis in resected patients revealed that multiple tumors (p < 0.0074) and non-curative resection (p = 0.0068) were significant risk factors for poor overall survival. The survival rate in patients with three or more positive nodes was significantly lower than in those with fewer than three (p < 0.0001). Three patients with solitary tumors and one or two involved lymph nodes have survived beyond 4 years after extended lobectomy with systemic lymphadenectomy. Curative resection, single tumor, and fewer than two lymph node metastases were prognostic factors for good outcome. Curative resection with lymph node dissection improved survival in patients with no more than two positive lymph nodes.

Adult↗
PubMed2005

Postoperative portal and splenic vein thrombosis in children: identification of risk factors.

Postoperative portal and splenic vein thrombosis (PSVT) is a rare but potentially fatal complication after abdominal surgery. We present 2 infants with PSVT after splenectomy and total colectomy, respectively, and also provide a review of the literature. We conclude that clinicians should consider that PSVT might occur after splenectomy for a huge splenomegaly or after a total colectomy for ulcerative colitis.

Adolescent↗
PubMed2005

Laparoscopic hepatectomy with the hook blade of ultrasonic coagulating shears and bipolar cautery with a saline irrigation system.

BACKGROUND: The number of patients who have undergone laparoscopic hepatectomy is small, and the operative procedure is not yet well established. METHODS: We performed laparoscopic hepatectomy in eight patients, using the hook blade of ultrasonic coagulating shears, and bipolar cautery with a saline irrigation system, with minilaparotomy. The operative time, blood loss, and postoperative hospital stay of patients with laparoscopic left lateral segmentectomy were compared with these parameters in ten patients who had had a left lateral segmentectomy with laparotomy. RESULTS: The laparoscopic hepatectomies included seven left lateral segmentectomies and one nonanatomical partial resection of the lateral segment. The mean duration of the operation in these eight patients was 181.1 +/- 44.6 min. The mean amount of blood loss was 177.6 +/- 129.1 ml. Postoperative complications consisted of two cases of bleeding. The mean postoperative hospital stay in all eight patients was 9.88 +/- 4.36 days. The mean duration of operation (185.9 +/- 46.0 min) and mean postoperative hospital stay (9.47 +/- 4.61 days) in the seven patients with laparoscopic left lateral segmentectomies were significantly shorter than these parameters (255.7 +/- 59.4 min and 24.6 +/- 8.82 days) in the ten patients who had had left lateral segmentectomies with laparotomy. The mean amount of blood loss (160.0 +/- 128.9 ml) in the laparoscopic series was less than that (318.5 +/- 192.2 days) in the patients who had had laparotomy. CONCLUSIONS: Laparoscopic hepatectomy with the ultrasonic coagulating shears and bipolar cautery with minilaparotomy was safe, and less invasive than the open procedure, for minor hepatectomy procedures such as left lateral segmentectomy.

Aged↗